Persistent disease activity (PDA) in spite of anti-vascular endothelial growth factor (VEGF) therapy remains a significant clinical unmet need for patients with neovascular age-related macular degeneration (NVAMD). The purpose of this STTR Phase I grant application is to develop novel therapies that will be effective for the treatment of PDA associated with NVAMD. The current proposal represents a collaboration between Eyedesis Biosciences, LLC, a spinout biotechnology company focused on retinal diseases, and a Collaborative Team of investigators from Eye, Pharmacology, and Medicinal Chemistry at Duke University School of Medicine. This team has established that the primary cause of PDA in the clinic is neovascular remodeling (NVR), and that NVR appears to be mediated by blood-derived macrophages in experimental models of NVAMD. The Pharmacology Team has identified calcium / calmodulin-dependent protein kinase kinase 2 (CaMKK2) as a key regulatory kinase that amplifies macrophage effector function. A collaborative effort of Eye and Pharmacology has demonstrated that both genetic deletion and local pharmacologic inhibition of CaMKK2 prevents the development of NVR in experimental NVAMD. The Medicinal Chemistry team has designed and initiated the synthesis of novel small molecule inhibitors of CaMKK2 for the treatment of NVAMD and other retinal diseases with macrophage-mediated pathobiology. Funded by an internal Duke Translational Research Institute seed-fund grant, this Collaborative Team of investigators has performed critical work to establish 1) CaMKK2 as a potential therapeutic target for NVAMD, and 2) a viable drug development initiative with Duke- owned novel intellectual property (IP). Eyedesis Biosciences was founded to formalize this initiative as a commercial drug development program following IP outlicense. The proposed STTR Phase I project will attempt to achieve four key milestones: (1) Novel small molecules are potent inhibitors of macrophage CaMKK2 and effector function in vitro; (2) These small molecules are more selective for CaMKK2 than STO-609 with less off-target activity; (3) The small molecules are well tolerated when injected around the eye (i.e. subconjunctivally); and (4) Subconjunctival ocular administration of these compounds is effective in preventing NVR. The key deliverable will be the identification of at least one small molecule that meets these goals. Successful realization of the Phase I milestones will justify additional development in Phase II, including: (1) nomination of lead candidate(s) for intravitreal therapy; (2) clinical formulation for intravitreal injection of candidate drugs; (3) performance of IND-enabling studies (i.e. GLP toxicology and PK) for injectable therapies.